In adulthood, there is a high comorbidity between major depressive disorder (MOD) and risk for cardiovascular disease (CVD), two of the leading causes of disability and mortality worldwide. This application will test hypotheses that there are shared prenatal antecedents to these disorders which will contribute to understanding their etiology and co-occurrence in adulthood. Research has demonstrated significant associations between cytokines (TNF-a, IL-1P, IL-6, CRP), HPA hormone abnormalities and MOD and CVD risk. Our hypotheses about fetal antecedents are based on evidence that some of the major brain regions involved in regulating affect are also involved in inflammatory responses, the HPA axis, and ANS which controls the heart's R-R interval variability (RRV) and blood pressure. We propose that HPA hormones and cytokines TNF-a, IL-1P, IL-6 that these shared brain regions express are the critical links between MOD and CVD risk, beginning during prenatal development. Our primary aims are to test for the: 1) association between elevated maternal-fetal cytokine levels and MOD & CVD risks; 2) associations between elevated maternal-fetal cytokines and adult offspring's HPA axis, cytokines TNF-a, IL-1(3, IL-6, CRP, and the heart's R-R interval variability (RRV) abnormalities (factors in the hypothesized pathway to MOD and CVD Co- morbidity); and 3) extent to which the associations between elevated maternal-fetal cytokines and MOD and CVD risks are mediated by offspring's HPA, cytokine, and RRV abnormalities. We will use data derived from the New England cohort of the National Collaborative Perinatal Project and the California Child Health & Development Study, which have rich and comparable pregnancy & developmental data and archived sera from pregnancy. 350 same-sex sibling sets, gestational ages 38-42 weeks and now ages 39-47, will be sampled who are discordant for either fetal growth restriction (n=175 sets) or pre-eclampsia (n=175 sets), two exposures significantly associated with substantial variation in elevated maternal-fetal cytokines. We will evaluate these subjects in adulthood to relate adult HPA, RRV and cytokine abnormalities as mediators of the association between fetal cytokine abnormalities with adult MOD and CVD risks. Findings will have important implications for understanding the etiology of MOD and CVD co-morbidity and the potential development of hormonal or immunoregulatory interventions to prevent them during fetal development. [unreadable] [unreadable] [unreadable]